Identification of<i>Chlamydia trachomatis</i>Antigens Recognized by T Cells From Highly Exposed Women Who Limit or Resist Genital Tract Infection

Russell, Ali N.; Zheng, Xiaojing; O’Connell, Catherine M.; Wiesenfeld, Harold C.; Hillier, Sharon L.; Taylor, Brandie D.; Picard, Michelle D.; Flechtner, Jessica B.; Zhong, Wujuan; Frazer, Lauren C.; Darville, Toni

doi:10.1093/infdis/jiw485

Cited by 43 publications

(34 citation statements)

References 35 publications

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“…We next investigated the association between chlamydia load and ascension. Cervical burden was significantly lower in 56 women with cervical infection only, compared to 39 women with endometrial infection ( P = 3.51E‐08, t test; Figure ), consistent with prior findings within the cohort . Finally, we performed a causal mediation analysis to test whether antibody impacted ascension (Figure ).…”

Section: Resultssupporting

confidence: 80%

“…Cervical and endometrial swab samples were tested for C trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium using nucleic acid amplification tests (NAAT; Aptima Combo 2; Gen‐Probe, and APTIMA MG; Gen‐Probe) as described previously . Cervical chlamydia burden was estimated via quantitative PCR using genomic DNA extracted from reserved cervical swab eluates as template . Women with positive cervical and endometrial Chlamydia NAATs were designated Endo+, while those with a positive cervical NAAT only were defined as Endo−.…”

Section: Methodsmentioning

confidence: 99%

“…We previously investigated the role for anti‐chlamydia EB IgG in limiting chlamydial infection . We observed both that serum titers of anti‐EB IgG were associated with reduced cervical burden, and that women with lower cervical burden were at reduced risk for endometrial infection . Paradoxically, anti‐EB IgG titers failed to correlate with absence of endometrial infection .…”

Section: Introductionmentioning

confidence: 99%

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Anti‐chlamydia IgG and IgA are insufficient to prevent endometrial chlamydia infection in women, and increased anti‐chlamydia IgG is associated with enhanced risk for incident infection

Darville

Albritton

Zhong

et al. 2019

American J Rep Immunol

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Problem Chlamydia infections in women can ascend to the upper genital tract, and repeated infections are common, placing women at risk for sequelae. The protective role of anti‐chlamydia antibodies to surface exposed antigens in ascending and incident infection is unclear. Method of study A whole‐bacterial ELISA was used to quantify chlamydia‐specific IgG and IgA in serum and cervical secretions of 151 high‐risk women followed longitudinally. Correlations were determined between antibody and cervical burden, and causal mediation analysis investigated the effect of antibody on ascension. We examined the relationship of antibody to incident infection using the marginal Cox model. Results Serum and cervical anti‐chlamydia IgG and cervical IgA levels correlated inversely with cervical burden. While lower burden was associated with reduced ascension, causal mediation analysis revealed that the indirect effects of antibody mediated through reductions in bacterial burden were insufficient to prevent ascension. Analysis of women uninfected at enrollment revealed that serum and cervical anti‐chlamydia IgG were associated with increased risk of incident infection; hazard ratio increased 3.6‐fold (95% CI, 1.3‐10.3), and 22.6‐fold (95% CI, 3.1‐165.2) with each unit of serum and cervical IgG, respectively. Conclusion Although anti‐chlamydia IgG and IgA correlated with reduced cervical chlamydia burden, they failed to prevent ascension and increased levels of anti‐chlamydia IgG were associated with increased risk for incident infection.

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Section: Resultssupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anti‐chlamydia IgG and IgA are insufficient to prevent endometrial chlamydia infection in women, and increased anti‐chlamydia IgG is associated with enhanced risk for incident infection

Darville

Albritton

Zhong

et al. 2019

American J Rep Immunol

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“…Some T3SS proteins are surface-exposed and can be targeted by neutralizing antibodies. The T cell response to T3SS antigens was recently shown to be associated with protection against C. trachomatis infection in highly exposed women [13], and T3SS components have recently attracted attention as vaccine candidates against other pathogenic bacteria [14–17]. The C. trachomatis T3SS filament protein, CdsF, and its orthologs in other bacteria form the needles of injectisomes and are believed to facilitate the insertion of translocators into the host cell membrane [11, 12, 18].…”

Section: Introductionmentioning

confidence: 99%

Chlamydial Type III Secretion System Needle Protein Induces Protective Immunity againstChlamydia muridarumIntravaginal Infection

Koroleva

Kobets

Щербинин

et al. 2017

BioMed Research International

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Chlamydia trachomatis imposes serious health problems and causes infertility. Because of asymptomatic onset, it often escapes antibiotic treatment. Therefore, vaccines offer a better option for the prevention of unwanted inflammatory sequelae. The existence of serologically distinct serovars of C. trachomatis suggests that a vaccine will need to provide protection against multiple serovars. Chlamydia spp. use a highly conserved type III secretion system (T3SS) composed of structural and effector proteins which is an essential virulence factor. In this study, we expressed the T3SS needle protein of Chlamydia muridarum, TC_0037, an ortholog of C. trachomatis CdsF, in a replication-defective adenoviral vector (AdTC_0037) and evaluated its protective efficacy in an intravaginal Chlamydia muridarum model. For better immune responses, we employed a heterologous prime-boost immunization protocol in which mice were intranasally primed with AdTC_0037 and subcutaneously boosted with recombinant TC_0037 and Toll-like receptor 4 agonist monophosphoryl lipid A mixed in a squalene nanoscale emulsion. We found that immunization with TC_0037 antigen induced specific humoral and T cell responses, decreased Chlamydia loads in the genital tract, and abrogated pathology of upper genital organs. Together, our results suggest that TC_0037, a highly conserved chlamydial T3SS protein, is a good candidate for inclusion in a Chlamydia vaccine.

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“…A small study of adolescent women demonstrated that IFN-γ production by CD4 + T-cells trended towards a reduced risk for reinfection [8]. Another study showed an increased in the frequency of IFN-γ-producing CD4 + T-cells in women without incident CT infection compared to women with CT infection [9]. Further support for the protective role of IFN-γ comes from an immunoepidemiologic study of commercial sex workers that showed a reduced risk for incident Ct infection was associated with the Th1 cytokine IFN-γ and also the Th2 cytokine IL-13 [10].…”

Section: Introductionmentioning

confidence: 99%

Stimulated peripheral blood mononuclear cells from chlamydia-infected women release predominantly Th1-polarizing cytokines

et al. 2019

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Chlamydia trachomatis infection (chlamydia) is the most prevalent sexually transmitted bacterial infection and causes significant reproductive morbidity in women. Little is known about how immunity to chlamydia develops in women, though animal models of chlamydia indicate that T-helper type 1 (Th1) responses are important for chlamydia clearance and protective immunity, whereas T-helper type 2 (Th2) responses are associated with persisting infection. In chlamydia-infected women, whether the predominant immune response is Th1- or Th2-polarizing remains controversial. To determine the cytokine profiles elicited by peripheral blood mononuclear cells (PBMCs) from chlamydia-infected women, we stimulated PBMCs with C. trachomatis elementary bodies and recombinant C. trachomatis Pgp3 and measured supernatant levels of select cytokines spanning Th1- and Th2-polarizing responses. We found that stimulated PBMCs from chlamydia-infected women secreted cytokines that indicate strong Th1-polarizing responses, especially interferon-gamma, whereas Th2-polarizing cytokines were expressed at significantly lower levels. In chlamydia-infected women, the predominant cytokine responses elicited on stimulation of PBMCs with C. trachomatis antigens were Th1-polarizing, with interferon-gamma as the predominant cytokine.

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Identification ofChlamydia trachomatisAntigens Recognized by T Cells From Highly Exposed Women Who Limit or Resist Genital Tract Infection

Abstract: Investigations in naturally exposed women reveal protective responses and identify chlamydial vaccine candidate antigens.

Cited by 43 publications

References 35 publications

Anti‐chlamydia IgG and IgA are insufficient to prevent endometrial chlamydia infection in women, and increased anti‐chlamydia IgG is associated with enhanced risk for incident infection

Anti‐chlamydia IgG and IgA are insufficient to prevent endometrial chlamydia infection in women, and increased anti‐chlamydia IgG is associated with enhanced risk for incident infection

Chlamydial Type III Secretion System Needle Protein Induces Protective Immunity againstChlamydia muridarumIntravaginal Infection

Stimulated peripheral blood mononuclear cells from chlamydia-infected women release predominantly Th1-polarizing cytokines

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